Synthetic oligonucleotides are currently attracting considerable attention as probes for molecular biology and as potential therapeutic agents. See C. Marcus-Sekura, 172 Anal. Biochem. 289 (1988); F. Eckstein, 22 Angew Chem., Int. Ed. 423 (1983); F. Eckstein, 54 Ann Rev. Biochem. 367 (1985); M. Hamblin et al., 241 Biochem. J. 827 (1987); R. Letsinger et al., 110 J. Am. Chem. Soc. 4470 (1988); P. Miller et al., in Nucleic Acids; The Vectors of Life, 521 (B. Pullman and J. Jortner Eds., 1983); P. Miller and P. Ts'so, 2 Anticancer Drug Design 117 (1987); P. Sarin et al., 85 Proc. Natl. Acad. Sci. U.S.A. 7488 (1988); M. Matsukura et al., 86 Proc. Natl. Acad. Sci. U.S.A. 4244 (1989); C. Smith et al., 83 Proc. Natl. Acad. Sci. U.S.A. 2787 (1985); S. Agrawal et al., 85 Proc. Natl. Sci. U.S.A. 7079 (1988). Thus, oligonucleotides with modified backbones, also known as "antisense" agents, may be used to inhibit or control growth of viruses as well as to specifically control the expression of genes concerned with genetic disorders.
The naturally occuring oligonucleotides and oligodeoxynucleotides contain an internucleotide phosphodiester linkage of the formula: ##STR2## Several modifications of the internucleotide phosphodiester linkage have been made. Exemplary is the methylphosphonate, which has the formula: ##STR3## See P. Miller et al., 18 Biochemistry 5134 (1979). Other modifications which have been made include the phosphotriester (--P--OR), See P. Miller et al., 93 J. Am. Chem. Soc. 6657 (1971); the phosphorothioate (--P--S), See P. Burgers and F. Eckstein, 18 Biochemistry 592 (1979), the phosphorodithioate (S--P--S), See W. Brill et al. 111 J. Am. Chem. Soc. 2321 (1989), and the phosphoramidate (--P--NR.sub.2), See K. Ogilvie and J. Nemer, 21 Tetrahedron Lett. 4145 (1988). Such modified oligonucleotides have been shown to inhibit viruses such as HIV, HSV, etc., and the expression of oncogenes such as c-myc and c-Ha-ras. See C. Stein and J. Cohen, 48 Cancer Res. 2659 (1988); C. Markus-Sekura et al. 15 Nucl. Acids Res. 5749 (1987); R. Meikkila et al., 328 Nature 445 (1987).
While it is clear that considerable potential exists for modified oligonucleotides as both probes and potential therapeutic agents, it is equally clear that a considerable effort is required to translate this field into new and useful compounds. The present invention arose from our ongoing research into new oligonucleotides useful as gene probes and as potential therapeutic agents.